Jeong Mi-So, Baek Seung-Woo, Yang Gi-Eun, Mun Jeong-Yeon, Kim Jeong Ah, Kim Tae-Nam, Nam Jong-Kil, Choi Yung-Hyun, Lee Ju-Seog, Chu In-Sun, Leem Sun-Hee
Department of Biomedical Sciences, Dong-A University, Busan, 49315, South Korea; Research Center, Dongnam Institute of Radiological & Medical Sciences (DIRAMS), Busan, 46033, South Korea.
Aging Convergence Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, 34141, South Korea.
Cancer Lett. 2025 Feb 1;610:217339. doi: 10.1016/j.canlet.2024.217339. Epub 2024 Nov 26.
Non-muscle-invasive bladder cancer (NMIBC) often recurs and can progress to MIBC due to resistance to treatments like intravesical chemotherapy or Bacillus Calmette-Guérin (BCG). Therefore, we established the Gemcitabine-Resistant Cells (GRCs) to study the molecular evolution under external pressure. A 63-gene Chemoresistance-Motility (CrM) signature was created to identify stage-specific traits of GRCs. This signature was tested on 1846 samples using log-rank tests and Cox regression to evaluate clinical utility. Early and intermediate resistance stages showed increased cell motility and metastatic potential. FAK, PI3K-AKT, and TGFβ pathways were activated first, followed by MAPK signaling. Single-cell analysis and experiments utilizing the CrM signature confirmed interaction with cancer-associated fibroblasts (CAFs). The high-CrM groups mainly included NMIBC patients with poor prognosis (progression-free survival analysis by log-rank test based on UROMOL cohort, p < 0.001), T1-high grade, high European Association of Urology (EAU) risk score, and also included MIBC patients with a history of metastases. Additionally, relative ineffectiveness was observed for BCG (the chi-square test based on BRS cohort, p = 0.02) and immune checkpoint inhibitors (ICIs) in patients with high-CrM. In addition, we identified five drugs that can be used with gemcitabine in these patients, including doxorubicin, docetaxel, paclitaxel, napabucacin, and valrubicin, and verified their efficacy. This study provides insights into NMIBC progression to MIBC via molecular evolution. The CrM signature can assess NMIBC prognosis and BCG treatment response, suggesting alternative treatments. Furthermore, these results need to be prospectively validated.
非肌层浸润性膀胱癌（NMIBC）常复发，且由于对膀胱内化疗或卡介苗（BCG）等治疗产生耐药性，可能进展为肌层浸润性膀胱癌（MIBC）。因此，我们建立了吉西他滨耐药细胞（GRCs），以研究外部压力下的分子进化。创建了一个63基因的化疗耐药-运动性（CrM）特征，以识别GRCs的阶段特异性特征。使用对数秩检验和Cox回归对1846个样本进行该特征测试，以评估其临床实用性。早期和中期耐药阶段显示细胞运动性和转移潜能增加。FAK、PI3K-AKT和TGFβ信号通路首先被激活，随后是MAPK信号通路。单细胞分析和利用CrM特征的实验证实了与癌症相关成纤维细胞（CAF）的相互作用。高CrM组主要包括预后不良的NMIBC患者（基于UROMOL队列的对数秩检验无进展生存分析，p<0.001）、T1高分级、高欧洲泌尿外科学会（EAU）风险评分患者，还包括有转移史的MIBC患者。此外，在高CrM患者中观察到BCG（基于BRS队列的卡方检验，p = 0.02）和免疫检查点抑制剂（ICI）相对无效。此外，我们确定了五种可与吉西他滨联合用于这些患者的药物，包括阿霉素、多西他赛、紫杉醇、萘布卡星和表柔比星，并验证了它们的疗效。本研究通过分子进化深入了解了NMIBC向MIBC的进展。CrM特征可评估NMIBC预后和BCG治疗反应，提示替代治疗方法。此外，这些结果需要前瞻性验证。
